JP2019108366A - Tablet formulation for cgrp active compounds - Google Patents

Abstract

To provide a formulation that facilitates dissolution and enhances oral absorption.SOLUTION: The present invention is directed to compositions comprising an extrudate or solid solution of a compound, or a salt thereof, of formula I (API) in the figure, where "R" is independently H or -F, in a water-soluble polymer matrix, where the compositions further comprise a disintegration system allowing a tablet made thereof to rapidly disintegrate in an environment in which the API is to be released.SELECTED DRAWING: Figure 3

Description

CGRP (calcitonin gene related peptide) is a calcitonin messenger RNA
Is a naturally occurring 37 amino acid peptide produced by tissue specific selective processing of and is widely distributed in the central and peripheral nervous system. Calcitonin gene related peptide (
CGRP) is a potent vasodilator neurotransmitter thought to play an important role in the pathophysiology of migraine. The first human clinical evaluation of CGRP targets was Boeh in 2003
It was reported that an IV preparation provided by ringer Ingelheim and containing orsegepant was effective for acute treatment of migraine, and that the mechanism was confirmed by a test using telkage pantest (CGRP antagonist) in an oral preparation.

The newly developed CGRP antagonist compounds are disclosed in published WO 2012/130.
No. 064,910, based on the structure of formula I:

Formula I
(Wherein, “R ^a ” is various substituents (eg, “R ^a ” is hydrogen: (S) —N—
((3S, 5S, 6R) -6-methyl-2-oxo-5-phenyl-1- (2,2,2-)
Trifluoroethyl) piperidin-3-yl) -2'-oxo-1 ', 2', 5,7-tetrahydrospiro [cyclopenta [b] pyridine-6,3'-pyrrolo [2,3-b] pyridine] -3-carboxamide, for example, in the formula, three of “R ^a ” are fluorine: (S) —
N-((3S, 5S, 6R) -6-Methyl-2-oxo-1- (2,2,2-trifluoroethyl) -5- (2,3,6-trifluorophenyl) piperidine-3- Il)-2 '
-Oxo-1 ', 2', 5,7-tetrahydrospiro [cyclopenta [b] pyridine-6
, And selected to be 3'-pyrrolo [2,3-b] pyridine] -3-carboxamide). These compounds are promising as well-tolerated, potent CGRP antagonists with low potential for side effects and metabolic complications. However, these compounds are poorly soluble and
In general, they do not form salts suitable for the preparation of stable pharmaceutical formulations.

For initial in vivo testing, as a liquid formulation, eg as a co-solvent or PEG 40
It is common to administer poorly soluble "class II" compounds, formulated as lipid-based solutions, using co-solvents such as 0 and optionally other ingredients to facilitate dissolution and enhance oral absorption. is there. While useful for clinical trials, providing liquid formulations for oral delivery of agents for use in the treatment of acute or chronic disease states or in the prophylactic treatment of chronic disease states is generally not commercially attractive. Desirably, such pharmaceutical products should be in solid form for oral administration, eg, as pressurized tablets or capsules containing the API. However, in general, drugs with low water solubility are difficult to deliver to the gastrointestinal system without the presence of some solubility or permeation enhancers or both at the site of absorption.

Solid dispersions, and in particular solid solutions, are used to facilitate oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs). For example, Ford, Pharm Acta Helv,
1986, 61: 69-88. Solid dispersions and solid solutions are compositions in which the API is dispersed or dissolved in a solid matrix, generally a polymer matrix. (
Solid solutions and solid dispersions, in which the active pharmaceutical ingredient forms a homogeneous or nearly homogeneous glass in the excipient matrix, are of particular interest in the oral delivery of poorly water-soluble compounds. These materials can either (i) improve the wettability of the API, (ii) provide temporary supersaturation of the API at the saturation point with respect to the lower energy (eg crystalline) phase API, or (iii) both. The effect is believed to improve absorption of orally administered API. In general, it is believed that solid solutions allow for drug absorption by increasing the dissolution rate and / or the extent to which the drug is dissolved from the matrix.

One example of a class II drug that is prepared as a solid solution is posaconazole described in WO 2009/129300 published Oct. 22, 2009. Such a composition of posaconazole is prepared by forming an extrudate of posaconazole with hydroxypropyl methylcellulose acetate succinate derivatized polymer (HPMC-AS), said solid dispersion then being microcrystalline cellulose, additional HPMC -Mixed with AS, hydroxypropyl cellulose, and magnesium stearate. This mixture is
The tablet was tableted to provide an orally administrable posaconazole formulation having the desired PK and bioavailability.

Another example of a polymer and a polymer used in providing a solid solution of an API is a US patent that describes a solid dispersion comprising a poorly soluble drug (exemplified by theophylline) and a crosslinked polyvinylpyrrolidone / vinyl acetate copolymer (PVP copolymer) 4th, 801, 46
No. 0 reported by Goertz et al. The '460 patent reports drug release times of up to 8 hours in testing and does not discuss instant release pharmaceuticals using such polymer matrix solid solutions.

In another example, published WO 98/02 published July 9, 1998.
No. 9137 ('137), Takagi et al., Cellulosic polymers such as hydroxypropyl methylcellulose, hydroxyethyl cellulose and hydroxypropyl cellulose, and salts having an endotherm of dissolution, such as sodium bicarbonate which is said to improve the rate of disintegration. Describes a composition comprising an API dissolved in a matrix comprising
The '137 publication is taught in that publication to be similar to mixtures using carbonates or bicarbonates in the presence of a solid water-soluble acid which aids in disintegration when exposed to an aqueous environment via the foaming action. The composition has been identified.

In another example, Fry et al. Have been dispersed in a broad polymer matrix, including cellulosic polymers (including graft copolymers incorporating cellulosics), polyvinyl alcohol polymers and many different derivatives of polyvinyl pyrrolidine polymers. 2
Formulations of inhibitors are described. See published publication WO 2013/056108, published April 18, 2013. Such compositions are said to reduce inter-patient PK variability.

Despite their increased use, the design of solid solution formulations that effectively promote oral drug absorption remains largely a matter of trial and error. The successful preparation of lipophilic compounds as solid dispersions to facilitate oral absorption may benefit from the strong interaction of the API with the polymer. This is particularly of interest to partially water-soluble polymers with amphiphilic properties such as hydroxypropyl methylcellulose acetate succinate (HPMCAS), when the process used to make the solid dispersion is spray drying Brought Friesen et
al. , Mol. Pharm. , 2008, 5: 1003-1019. While this approach has been successful for many drug candidates, compounds with high melting points (or high ratio of melting point to glass transition temperature) and / or particularly lipophilic compounds (eg, those with high log P values) are successful as solid solutions It has been suggested that the preparation is particularly problematic for the preparation of salmon. Fr
suggest that the successful preparation of compounds having high melting point characteristics may be limited to relatively diluting the concentration of API in the solid dispersion.

International Publication No. 2012/064910 International Publication No. 2009/129300 U.S. Pat. No. 4,801,460 WO 98/029137 International Publication No. 2013/056108

Ford, Pharm Acta Helv, 1986, 61: 69-88. Friesen et al. , Mol. Pharm. , 2008, 5: 1003-1019

As understood from the above, for oral administration to be administered via the GI tract, it may be desirable to provide the compound of Formula I in solid form, but the nature of the treatment provided is necessarily Need to make the compound of formula I readily available to the patient. There are few currently reported immediate release formulations based on solid dispersions or solid solutions of class II API in polymer matrices.

In one aspect, the invention is a tablet,
(A) (i) a water soluble polymer matrix,
(Ii) a dispersant,
(Iii) a compound of formula I, or a pharmaceutically acceptable salt thereof:

An extrudate comprising the formula I, wherein “R ^a ” is independently —H or —F, and the dispersant and the compound of the formula I are dispersed in said polymer matrix,
(B) a tablet comprising a disintegration system,
Wherein said tablets have a hardness of about 12 kP to about 18 kP and an aqueous HC of 37 ° C.
provides a tablet wherein the tablet achieves complete disintegration in less than about 5 minutes in a standard tablet disintegration test according to USP 31-NF26 chapter 701 using l (pH 1.8).

In some embodiments, it is preferred that the water soluble polymer matrix of the extrudate is a polyvinyl pyrrolidone / vinyl acetate copolymer (PVP-VA) matrix.

In some embodiments, it is preferred that the disintegration system comprises powdered sodium chloride and croscarmellose sodium, more preferably in a 1: 1 weight ratio.

In some embodiments, it is preferred that the tablet have a hardness of about 12 kP to about 16 kP. In some embodiments, it is preferred that the tablet have a tensile strength of about 1.75 MPa.

In some embodiments, the tablet of the invention is a dissolution test according to USP 30 NF 25 Chapter 7 1 (apparatus with USP 2 paddle operated at 50 rpm in 900 ml of simulated gastric fluid (pH 1.8) at 37 ° C) When subjected to # 2), it is preferred to release at least about 90 wt% of the compound of formula I contained in the tablet.

In some embodiments, preferably the tablet is
Powdered sodium chloride characterized by (a) (i) d ₅₀ values of less than about 210 microns, (ii) d ₁₀ values of less than about 50 microns, and (iii) d ₉₀ values of less than about 470 microns.
(B) including a disintegration system comprising croscarmellose sodium,
Here, the powdered sodium chloride and the croscarmellose sodium are present in a 1: 1 weight ratio, and the amount of extrudate present in the tablet is about 9 wt. % To about 1
0 wt. It is chosen to provide% of the compound of formula I.

In some embodiments, the disintegration system comprises about 20 wt. It is preferable to constitute%. In some embodiments, the tablet comprises about 50 wt. % Of extrudates.

In some embodiments, a tablet formulation according to the invention comprises (i) an extrudate, (ii) a disintegrating system, and (iii) one or more diluents (in some embodiments as diluents) It is preferable to select mannitol and microcrystalline cellulose), (iv)
In some embodiments, it is preferred to use colloidal silica as a fluidizing agent, and (v) one or more lubricants (in some embodiments, sodium stearyl fumarate as a lubricant) Preferably used).

In some embodiments, it is preferred that the compound of Formula I is a compound of Formula Ia, or a salt thereof:

Formula Ia
(Wherein, “R ^b ” is each —H, or “R ^b ” is each -F).

In some embodiments, preferably the water soluble polymer matrix of the extrudate is a water soluble polyvinyl pyrrolidone / vinyl acetate copolymer, preferably produced by free radical polymerization of a 6: 4 ratio of vinyl pyrrolidone: vinyl acetate monomers. Polyvinyl pyrrolidone / vinyl acetate copolymer.

In some embodiments in which the compound of formula I is a compound of formula Ia, preferably
The compound of this invention is about 20 wt% of the extrudate to about 22 wt. % Is present in the extrudates.

In some embodiments, preferably the extrudate is at least about 5 wt% of the finished extrudate
. % Toceferol-polyethylene-glycol succinate (TPGS) is included as a dispersant.

In some embodiments, preferably the extrudate is about 50 wt. % To about 80 wt. %, Preferably about 70 wt. % To about 75 wt. And the soluble polyvinyl pyrrolidone / vinyl acetate copolymer present in an amount making up the%.

In one aspect the invention is a formulation suitable for providing a pressed tablet, comprising
a) Water soluble polyvinyl pyrrolidone / vinyl acetate copolymer (PVP-VA copolymer) matrix and dispersed therein:
(I) Active compound of formula Ia, or pharmaceutically acceptable salt thereof:

Formula Ia
(Wherein all of R ^b is either —H or all of R ^b is —F)
(Ii) an extrudate comprising toceferol polyethylene glycol succinate (TPGS), wherein said compound of formula Ia comprises from about 5 wt% to about 23 wt.
%, Wherein TPGS comprises at least about 5 wt. % Of the extrudate, and
a disintegration system comprising b) (i) croscarmellose sodium and (ii) powdered sodium chloride,
The disintegration system comprises about 20 wt. %, And the preparation is about 12 kP to about 18 kP
, Preferably characterized by providing a tablet having a hardness of about 12 kP to about 16 kP, USP operated at 50 rpm in 900 ml of simulated gastric fluid (pH 1.8) at 37 ° C.
The tablet is at least about 90% of the compound of Formula Ia contained therein when subjected to a dissolution test in accordance with USP 30 NF 25 Chapter 711 with a paddle stirrer equipped with two paddles.
And a disintegrating system that releases in less than about 20 minutes.

In some embodiments, the tablet formulation of the present invention is added to the extrudate and disintegrating system (i
) Mannitol (preferably about 20 wt.% Of the formulation), (ii) microcrystalline cellulose (preferably up to about 20 wt.% Of the formulation), and (iii) colloidal silica (preferably about 0.25 wt.% Of the formulation) And (iv) sodium stearyl fumarate (preferably about 0.75 wt.% Of the formulation). In some embodiments, preferably the tablet formulation is
About 50 wt. % Of said extrudates.

Figure 5 is a flow chart illustrating unit operations in the general preparation of the dispersion of the present invention. FIG. 5 is a flow chart illustrating unit operations in an alternative general preparation of a dispersion of the present invention. Fig. 5 is a flow chart illustrating unit operations in the preparation of the tablet of the present invention.

  The following terms that may be used herein are used in accordance with the following definitions.

All ranges cited herein are inclusive, unless expressly stated to the contrary.
That is, the range includes the upper and lower limits of the range as well as all values in between. By way of example, the temperature ranges, proportions, ranges of equivalents, etc., described herein include the upper and lower limits of the range and any values in the continuum therebetween.

The term "formulation" as used herein refers to a mixture, assemblage, solution or other combination of materials comprising an active pharmaceutical ingredient (API). The formulations are adapted to the particular mode of administration in the treatment, management, prevention, etc. of the pathological or disease states in the patient (eg, formulations suitable for compression into tablets designed for oral administration).

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human being the subject of treatment, observation or experiment. When human subjects suffering from a disease condition to be treated are involved in the activity, they are alternatively referred to herein as "patients".

As mentioned above, the present invention relates to a soluble polymer matrix and a compound of Formula I dispersed or dissolved therein, or a pharmaceutically acceptable salt thereof:

For an extruded composition (extrudate) comprising ^a formula I, wherein "R ^a " is independently -H or -F, and a dispersant, such as vitamin E polyethylene glycol succinate (TPGS) The extrudate is incorporated into a pharmaceutical formulation comprising a disintegrating system, which disintegrates within about 5 minutes in a standard disintegrating test, up to 18 kP hardness, preferably 16 k in some embodiments.
Suitable for providing tablets with P hardness.

Compounds of the formula I which are suitable for use in the composition according to the invention are disclosed in WO 2012/0649.
It can be prepared according to the synthesis described in No. 10. In some embodiments,
Crystallizing the crude compound of formula I prepared according to the above from an ethanol / water solvent, thus providing the crystalline trihydrate form of the compound, and putting it in the extruder apparatus used for the preparation of the dispersion It is preferred to grind the crystalline material to a particle size that provides a free flowing powder capable of As will be understood where noted, the weight and weight percent relationships described for the compounds of Formula I in the formulations and tablets described herein apply formulations with materials having less than 100% activity. As considered when preparing, it is adjusted to reflect the weight of the 100% active free base equivalent of the compound, without the solvent of crystalline or inert material.

Referring to FIGS. 1 and 2, generally, the extrudate is a compound of Formula I and a hot melt extrusion of various excipients that may or may not have received additional work to make it suitable for HME processing. Prepared by HME).

We surprisingly found that, contrary to the general experience with class II pharmaceutical compounds often dispersed in many different polymers as mentioned above, matrices comprising certain commercially available cellulosic polymers. It has been found that when it is attempted to incorporate a compound of formula I using the HME method, the compound of formula I tends to decompose thermally. For example, the use of HPMCAS as a polymer matrix results in the formation of excess degradation products in the prepared dispersion. In some experiments, the use of a cellulosic polymer as a dispersion matrix to prepare a dispersion of a compound of Formula I with HME reduces up to 25 times the amount of API degradation when subjecting the same thermal excursion to API alone. Brought.

Surprisingly, we have found that one type of commercially available polymeric material from which dispersions of the compound of formula I can be prepared without deteriorating the thermal decomposition of the compound is a commercially available water-soluble polymer, for example polyvinyl alcohol It was found to be a pyrrolidone / vinyl acetate copolymer (PVP-VA polymer). It is surprising that dispersions prepared by the HME method using water-soluble polymers, such as PVP-VA polymers and compounds of the formula I, do not lead to greater thermal decomposition of subjecting the raw compounds of the formula I alone to the same thermal excursion. It should have been found out. Thus, compounds of formula Ia in which the free base compound “FIa-H” (all of “R ^b ” is —H) or compounds of formula Ia in which the free base compound “FIa-F” (all of “R ^b ” is —F ) And a complete mixture of one of the two possible matrix polymers, 17
It was subjected to heating for 2 minutes to 0 ° C., then cooled to room temperature and evaluated spectroscopically for the formation of known thermal products. These data are summarized in Table I.

As exemplified in Table I, these data indicate that some commercially available cellulosic polymers exacerbate the thermal degradation of both FIa-H and FIa-F compounds. Furthermore, we have found that typically the HME processing temperature can reach 180 ° C., resulting in the loss of a much larger proportion of the compound of formula I to the degradation products. Therefore,
The inventors surprisingly found that polyvinylpyrrolidone / vinyl acetate copolymer (PVP-) using the hot melt extrusion (HME) processing method performed in the same thermal excursion used when cellulosic polymers are used. It has been found that dispersing the compound of formula I in a soluble copolymer of the VA copolymer) leads to a reduction of the degradation products detected in the extrudate product. Typically, the rate of increase of degradation products observed in such extrudates is the degradation product observed when a sample of the same compound of formula I is subjected to the same thermal excursion experienced in the HME process Was not greater than the percentage of

In accordance with the foregoing, a water soluble polymer suitable for use in the compositions of the present invention is any soluble PVP-VA copolymer made by free radical polymerization of a vinyl pyrrolidone: vinyl acetate monomer in a ratio of 6: 4. An example of a commercially available copolymer of this type is the trade name Koll
Polyvinyl pyrrolidone / vinyl acetate copolymer sold under idon® 64, and the like.

In addition to the matrix polymer and the at least one compound of formula I, the extrudates of the invention will contain some amount of excipients that act as dispersants. As the term is used herein, the dispersing agent drives the compound of formula I into the matrix polymer solution, and of the dispersion with even lower degradation losses of the compound of formula I dispersed in the matrix The thermal energy required to promote formation can be reduced. With regard to the extrudates of the present invention, in some embodiments vitamin E is present in its polyethylene glycol succinate (herein d-alpha-tocopheryl polyethylene glycol succinate,
Or in the form of TPGS). Examples of commercially available TPGS suitable for use in the extrudates of the present invention are anything that provides polyethylene glycol 1000 esterified d-alpha-tocopheryl succinate, eg, Eastman C
Vitamin E d-TPGS NF manufactured by hemical Company, but
It is not limited to this. In some embodiments, preferably TPGS is used as a dispersant, and at least about 5 wt. Is present in an amount that is%.

It will be appreciated that other dispersants such as polyethoxylated castor oil (eg Cremophor) may also be used.

Wt. Of extruded composition (extrudate). The relative amounts of compound of Formula I, matrix polymer and dispersant used in the compositions of the present invention, expressed as% may be different and still be within the scope of the present invention. Typically, the matrix polymer has an API and a dispersant w
t. After subtraction of%, it is present in an amount to compensate for the difference in composition. Typically, the amount of matrix polymer is about 70 wt. % To 75 wt. %. In some embodiments, the composition of the present invention, when corrected for relative activity as compared to the 100% pure free base compound of Formula I, is 25 wt% of the 100% free base compound contained within the finished extrudate composition. . It is preferred to include an amount of compound of formula I equal to less than or equal to%. In some embodiments, preferably
The amount of compound of formula I present in the finished extrudate is, by activity, about 5 wt.% Of 100% pure free base compound in the finished extrudate. % To about 22 wt. %, And more preferably at least about 20 wt.% Of the 100% free base compound in the finished extrudate in activity. It is an amount equal to%.

The composition of the present invention is a polymer matrix with a selected API (eg, a compound of Formula Ia) such that the drug is a uniform dispersion, generally amorphous, in or dissolved in the polymer. It can be prepared by a process suitable for forming a dispersion throughout. Generally, this involves some method of heating and combining the components of the desired composition and recovering the dispersion or solution in solid form. It will be understood that any means of obtaining a dispersion may be used without departing from the invention, but in some embodiments preparing a composition of the invention by hot melt extrusion (HME) Is preferred. Hot melt extrusion (HME) forms the finished composition dispersion or solution into a "noodle" or other conveniently handled shape that can be used for further processing in the preparation of tableting formulations (extrudates) While the extruder, eg, 27 mm Leistri
A tz twin screw extruder is the procedure used to mix and heat polymers, drugs, and dispersants.

In performing such operations, some or all of the components are blended, mixed or in a granulation process before being introduced into the extruder, for example, mixing of the dry powder or wetting of the components The comminution may be premixed by grinding or wet mixing the ingredients together to ensure intimately mixed ingredients that result in a uniform mixture of ingredients as the mixture is fed into the extruder. Alternatively, the components may be fed into the extruder using a separate feed stream (Polymer Extrusion 4 ^th Edition b
y Chris Rauwendaal 2001, Hanser Gardner P
ublications, Inc. , Cincinnati, OH, or Schenc
k et al. , (2010), Achieving a Hot Melt Ext
collision Design Space for the Production o
f Solid Solutions, in Chemical Engineerin
g in the Pharmaceutical Industry: R & D to
Manufacturing (ed. D. J. am Ende), John Wiley
& Sons, Inc. , Hoboken, NJ, USA). For some of the compositions of the present invention it is preferred to use the HME process to prepare them, but the composition of the present invention is a mixture of compound of formula I, matrix polymer and dispersant heated, mixed, It will be appreciated that it can be prepared by any means useful for preparing the melt on any convenient equipment that can be recovered.

Generally, when extruding the material, the act of transporting the material through the extruder results in the material being provided with energy that is converted to heat in the transport material. If the heat transfer from the extruder output consumed in material transport alone is not sufficient to obtain the temperature required to make the desired dispersion or solution of the compound of formula I with the polymer matrix, in general In essence, the extruder barrel is provided with a means to provide additional heat to the material. Similarly, different sections of the extruder barrel may be heated or cooled as needed to maintain a specific temperature within one section of the extruder barrel, or even to cool the material as it passes The heat of different sections of the extruder barrel may be removed to do so. In general, the extruder temperature, power and extruder transport speed are the minimum required to ensure that a uniform dispersion or solution is prepared, thus minimizing the amount of API that is subject to degradation during processing. Set to provide temperature excursions and dwell times.

Generally, the extrudate exiting the extruder is in a plastic state and hardens upon exiting the barrel by pressure release and cooling. During this transition, the extrudate typically has a contour shape, eg, noodles, bars, cylinders, etc., and is trimmed to a convenient length. Once the extrudate pieces are obtained, they can be further processed mechanically, for example by grinding, grinding or sieving to obtain a convenient form for incorporation into the dosage form. As the term is used herein, the material emerging from the extruder and then any form given to the material by mechanical processes, eg grinding, grinding, mixing, sieving or granulation , "Extrudates". Exemplary extruders include those provided by Leistritz, such as 27 mm Leistri.
tz twin screw extruders, and those provided by Thermo-Fisher, eg 1
A 6 mm twin screw Thermo-Fisher extruder is included. The apparatus generally comprises means for heating the extruder barrel for use in a "hot melt extrusion" operation.

Once the extrudate is in a convenient form for further processing, the extrudate is used for the preparation of a formulation for use in providing a dosage form suitable for oral administration, such as pressing into tablets or filling into capsules. It can be incorporated into a compatible formulation. In order to achieve the dissolution and disintegration goals necessary to effectively administer the compound of formula I in providing a treatment for migraine, a formulation comprising the finished extrudate is prepared, preferably milled, And disintegrating systems of the present invention, as well as other excipients useful for the preparation of formulations suitable for tableting, such as powder forms which are easily mixed with diluents and lubricants. For use in the formulations of the present invention, the disintegrating system may be a conventional disintegrant, such as croscarmellose sodium or crospovidone, and powdered chloride if "powdered sodium chloride" has the meaning indicated herein. Contains sodium.

For use in the disintegrating system of the present invention, the phrase "powdered sodium chloride" has the following values:
(I) d ₅₀ less than about 210 microns, eg, about 195 microns, (ii) d ₁₀ less than about 50 microns, eg, 43 to 44 microns, (iii) d ₉₀ less than about 470 microns, eg, about By sodium chloride processed to a form having a particle distribution that results in 460 microns, and the material exhibits a volume average diameter of less than about 240 microns, eg, about 230 microns. An example of one such type of sodium chloride that is commercially available is provided by Avantor® under the product designation “Sodium Chloride, Powder, USP GenAR® Product No. 7540”.

The data presented in Table II illustrate the need to use powdered sodium chloride in the disintegrating system in the formulations of the present invention. Thus, the extrudates according to the invention (PVP-VA matrix, compounds of the formula Ia (FIa-H), and said extrudates comprising TPGS), diluents comprising microcrystalline cellulose, and croscarmellose sodium and the left hand of Table II The test tablets containing a disintegration system consisting of the salts indicated in column of column are treated with aqueous HCl (pH 1.8) as disintegration medium
In a standard disintegration test apparatus (Pharamatron DT50) using
P 31-NF 26 was subjected to the disintegration test in accordance with Chapter 701. Surprisingly, only tablets using powdered sodium chloride in the disintegrating system, as reflected in Table II,
It was possible to meet disintegration goals of less than a minute (table compression force controlled to provide tablets of consistent hardness and thickness for all formulations).

In addition, when equivalent tablets were made with powdered sodium chloride alone without croscarmellose sodium, the tablet disintegration time was also found to exceed 5 minutes. Thus, in some embodiments, it is preferred that the disintegrating system comprises conventional disintegrants in combination with powdered sodium chloride, and more preferably powdered sodium chloride: disintegrant, in a weight ratio of 1: 1. It is believed that powdered sodium chloride exhibits rapid dissolution kinetics relative to the rate of gelation of the polymer matrix when exposed to the intended dissolution environment (human GI tract) without being subjected to Be Further, without being bound by theory, powdered sodium chloride, due to its particulate profile, has desirable dissolution kinetics, and sufficient speed (faster than the rate of gelation of the matrix polymer) locally of sufficient ionic strength With the combined ability to form a boundary layer to inhibit gel formation in the matrix polymer and thereby facilitate release of the compound of formula I from the tablet formulation otherwise inhibited by gel formation in the matrix polymer Conceivable. The invention as defined herein provided that it exhibits the same combination of rapid dissolution kinetics, and the ability to rapidly form a local boundary layer of sufficient ionic strength to inhibit gelation. It will be appreciated that other salts may be used in the formulations of the present invention without departing from the scope of the invention.

In the formulations of the present invention, suitable disintegrants for use in the disintegrating system of the present invention are, for example, croscarmellose sodium (crosslinked carboxymethylcellulose sodium polymer), for example the polymer AC-Di-Sol (available from FMC) It is a registered trademark system. Other disintegrants, such as crospovidone, are used to provide an effective disintegrating system, in accordance with other aspects of the disintegrating system described herein, without departing from the scope of the present invention. It will be understood that it is also good.

The compounds of formula I relate to the treatment of migraine headaches, so a rapid release formulation is considered important in providing therapeutic benefit to human patients to which such tablets are administered.

As is known, the two properties of tablet and capsule dosage forms that are important for the release of active pharmaceutical compounds are to be demonstrated using standard tests to determine the disintegration and / or dissolution time of the dosage form it can. The disintegration test measures the time it takes for the dosage form to visibly disintegrate and wash out from a standard basket contained in a standard device under standard operating conditions. Standard disintegration tests are described for tablets and capsules in USP 31-NF26, chapter 701, beginning on page 266. For example, there are the European Pharmacopoeia and its equivalents listed in the Japanese Pharmacopoeia, and standard tests are generally approved by regulatory agencies in most countries. When "disintegration time" is used herein for the formulations and tablets of the invention, the term follows the test according to this standard run at 37.degree. C. using aqueous HCl (pH 1.8) as the disintegration fluid It means that it was decided.

Dosage forms intended for oral administration can also be measured in dissolution tests, and time-rate release of the amount of therapeutic compound dissolved in the standard vehicle of a standard device introduced the dosage form into the test medium It will be measured later. Standard dissolution tests for tablets and capsules are described, for example, in US Pat. No. 36, 71.
It is described in Chapter 1. Comparable studies are given by the European and Japanese Pharmacopoeia and the US F.
Guidance from DA, eg U.S. S. Department of Health
and Human Services, Food and Drug Adminis
tration, Center for Drug Evaluation and R
"Guidance for Ind" published in August 1997 by esearch
ustry, Dissolution Testing of Immediate R
elease Solid Oral Dosage Forms ", pages 1-13, and references therein. When "disintegration time" is used herein for the formulations and tablets of the present invention, the term comprises 900 ml simulated gastric fluid (pH 1.8), USP 2 paddle operated at 50 rpm in 37 ° C. It means that it was determined according to the test based on this standard with a standard dissolution apparatus. ]
In one aspect, the present invention provides for the preparation of 90 of the API contained therein once the formulation has been pressed to have a hardness of about 12 kP to about 16 kP, and in some embodiments 12 kP to about 18 kP. Provide tablets that release more than 10% in less than about 20 minutes (U.
S. Department of Health and Human Service
Food and Drug Administration, Center fo
r "Guidance for Industry, Dissolution published in August 1997 by Drug Evaluation and Research
Testing of Immediate Release Solid Oral
900 ml simulated gastric fluid (pH 1.8), 50 rp in 37 ° C., according to the procedure outlined in the “Dosage Forms”, pages 1 to 13 and references therein in which the tablet hardness is exceeded.
when subjected to dissolution tests in a standard dissolution apparatus with a USP 2 paddle operated at m)
Formulation adapted for the preparation of tablets comprising, in amounts, the extrudates according to the invention, powdered sodium chloride and croscarmellose sodium, as well as other excipients, such as diluents, fluidizers and lubricants I will provide a.

When tablet hardness is used herein, it is for tablets having a 500 mg target weight and a 652.2 mg target weight in caplet or caplet form. Thus, as the term is used herein, a tablet having a hardness in the range of 12 kPa to 16 kPa has a corresponding tensile strength of about 1.75 MPa and a tablet having a hardness in the range of 19 kPa to 22 kPa , Has a tensile strength of about 2.75 Mpa.

The formulations of the present invention used for the preparation of oral dosage forms (ie tablets or capsules) may further comprise other excipients. For example, typical formulations of the present invention intended for the preparation of pressed tablets include diluents such as mannitol, commercial products, and / or microcrystalline cellulose such as Avicel®, fluidizers such as , Colloidal silica, eg Cab-
O-Sil (registered trademark), and a lubricant (eg, sodium stearyl fumarate, commercially available) may be contained. It will be appreciated that in the preparation of the compositions of the present invention, other diluents, glidants and lubricants may be substituted to yield similar formulations.

The following definitions, as the term is used herein, apply to excipients which can be used in the formulation of the invention.

Diluents are typically added in such a way that if the active pharmaceutical ingredient in the formulation is too strong to allow convenient processing or administration of the dosage form without diluent, or the formulation without the diluent alone is of the dosage form An excipient that adds bulk to the dosage form if it makes formation difficult (e.g., an aliquot of the formulation without a diluent is too small to form the aliquot into tablets).

Disintegrants are excipients which, when placed in an aqueous environment, such as the gastrointestinal tract, swell and / or dissolve, help break up the tablet and promote the release of the active pharmaceutical ingredient contained in the tablet.

A "disintegration system" is an environment in which the dosage form into which the disintegrating system is incorporated disintegrates, such as simulated gastric fluid,
It is a combination of a conventional disintegrant and a rapidly dissolving salt that provides a beneficial anti-gelling effect when placed in the subject's gastrointestinal tract or in an environment in aqueous HCl at pH 1.8.

The fluidizing agent is an excipient, such as colloidal silica, which reduces interparticle friction and enhances the flow of the particulate mixture.

Pharmaceutical formulations intended for the preparation of oral dosage forms (tablets and capsules) consist of the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives in order to provide a pharmaceutically excellent and palatable preparation It may further contain one or more agents selected.

Preparation of a formulation of the invention suitable for use in providing a solid oral dosage form comprising the composition of the invention compresses and / or removes the risk of separation of the components during subsequent manipulation (eg, compression into tablets). Alternatively, it may involve mixing, roller compaction or wet granulation to reduce. The granulation step can also be used to minimize the impact of raw material property variation (e.g., excipient particle size) on subsequent processing (e.g., tablet compression) and performance of the final product. Lubrication is typically performed prior to roller compression and tablet compression to reduce the tendency of the material to adhere to the compression surface (e.g., a tablet tool). Generally, the lubricant is a derivative of stearic acid, such as magnesium stearate or sodium stearyl fumarate.

Methods and methods useful for the preparation of dosage forms, such as Ansel, Introduction
to Pharmaceutical Dosage Forms, Seventh
It is known as described in Edition, 1999.

In general, the preparation of oral dosage forms from the pharmaceutical preparation of the invention consists in that the pharmaceutical preparation of the invention (mixture of excipients, disintegrating system and composition of the invention) is compressed into tablets or introduced into capsules Need. The tablets can be prepared in various possible shapes (elliptic, capsule, biconvex circle etc). Powders can also be encapsulated in capsule doses (eg, using hard gelatine capsules). A suitable procedure for the preparation of solid oral dosage forms of the invention is Remin
gton's Pharmaceutical Sciences, 18th edit
ion, edited by A. R. Gennaro, 1990, Chapter 8
9 and Remington-The Science and Practice o
f Pharmacy, 21st edition, 2005, Chapter 45. In some embodiments of the present invention, the tablet is a compound of Formula Ia (100
462.5 to 537.5 m, with the goal of providing 50 mg equivalents of
g of the preparation is placed in a tableting mold with Elizabeth Carbide Die CompanyTM, drawing number P-14305-B, which is pressed in a Korsch® tablet press and having a hardness of less than 16 kP It is preferred to prepare

Referring to FIG. 3, in general, the composition of the present invention is prepared by dry mixing various excipients with the milled dispersion (soluble polymer matrix containing API dispersed therein) and compressing the mixture into tablets .

The following is a description of the general procedure used in the preparation of extrudates, the preparation of tableting formulations comprising the extrudates, and the preparation of the tablets of the invention therefrom. The following examples serve only to illustrate the invention and its practice. The examples should not be construed as limitations on the scope or spirit of the invention.

[Example]
Example I
Kollidon (R) 64, TPGS and (S) -N-((3S, 5S, 6R)
) -6-Methyl-2-oxo-5-phenyl-1- (2,2,2-trifluoroethyl)
Piperidin-3-yl) -2'-oxo-1 ', 2', 5,7-tetrahydrospiro [cyclopenta [b] pyridine-6,3'-pyrrolo [2,3-b] pyridine] -3-carboxamide Preparation of extrudates containing (FIa-H), tablet formulations and tablets prepared therefrom:
Referring to FIG. 2, an extrudate comprising a water soluble polymer matrix and an API dispersed therein is:
(I) Dry blending of amounts of crystalline FIa-H and polyvinyl pyrrolidone / vinyl acetate copolymer (matrix polymer) to provide a pre-blend having a weight ratio of API: matrix polymer of 1: 3.75, FIa- H / forming a matrix polymer premix,
(Ii) API premix: TPGS, amount of API / matrix premix providing a weight ratio of 19: 1 and amount of molten alpha-tocopherol / polyethylene glycol succinate (TPGS) into the extruder, and (Iii) Barrel temperature to provide an extrudate comprising a solid solution of API in a matrix (polyvinylpyrrolidone-vinyl acetate copolymer / TPGS) comprising about 20 wt% active API,
Prepared by maintaining the extruder apparatus at the feed rate and screw speed.

Thus, 1.318 Kg of FIa-H (compound of Formula Ia where all " ^Rb " is -H) trihydrate was mixed with 4.382 Kg of matrix polymer. TPGS (0.30
0 Kg) was melted and added to the mixture of FIa-H and VA-64 in a high shear granulator. Using a Diosna high shear granulator with mixed API, VA-64, and TPGS, in a 6 L bowl, impeller speed of 1000 rpm, chopper speed of (600) rpm,
Prepared in eight separate mixes. The blender was run for 1 minute each time to mix the FIa-H and matrix polymer, and then molten TPGS was added by pipetting over 5 minutes while maintaining the impeller and chopper speeds. After TPGS addition, the mixture was mixed for an additional minute while maintaining the impeller and chopper speeds.

Product temperature of about 146 ° C. to about 160 ° C., die pressure of about 14 bar to about 16 bar, 3
Thermo-Fisch the mixture material while maintaining a powder feed rate of 0-52 g / min
er Put into a 16 mm extruder to obtain 6.0 kg of the inventive extrudate. Run this material on a Fitzmill with a screen diameter of 0 (0.027 '') under the following operating conditions: 2000-
Impeller speed of 4500prm, and shock: blade forward direction (forward blade
It grinds using direction). The milled extrudate material is passed through a 600 micron screen for use in the preparation of a mixture for compression molding into tablets (tablet mixture),
It was sized to provide a powder (extrudate intermediate) having a VMD of about 195 microns as measured by QICPIC.

A tableting mixture (6 kg) was dosed with 200 mg / g equivalents of 100% free base FIa-H, 1.1.
60 kg of mannitol SD10, 0.600 kg of sodium chloride powder, 0.600 k
g croscarmellose sodium, 0.01500 kg colloidal silica, 0.09
000 kg of sodium stearyl fumarate and 0.5798 kg of Avicel
Prepared using 3.6 kg of extrudate intermediate containing PH102. Blender speed is 25r
It was pm and the blender time was 5 minutes.

The tableting mixture is subdivided into 1.250 kg subparts, 12-16 kP, 19-22 kP,
And tablets corresponding to a hardness range of 24-28 kP, face drawing
) P14305-B, ie plain oval mold (14.68 mm × 8.33 mm) (pl
Aliquots from each portion of the tableting mixture were prepared by compression on a Korsch XI 100 equipped with upper and lower molds by the ain oval tool).

A tablet having a hardness in the range of 12 kP to 16 kP, 900 ml simulated gastric fluid (pH 1.
8) A paddle stirrer equipped with a USP 2 paddle operated at 50 rpm in 37 ° C.
It was tested according to the test according to USP 30 NF 25 Chapter 711. These tablets met the release profile goal of 90% FIa-F contained in tablets dissolved in less than 20 minutes.

Example II
Kollidon (R) 64, TPGS and (S) -N-((3S, 5S, 6R)
) -6-Methyl-2-oxo-1- (2,2,2-trifluoroethyl) -5- (2,3)
, 6-Trifluorophenyl) piperidin-3-yl) -2'-oxo-1 ', 2', 5
, 7-Tetrahydrospiro [cyclopenta [b] pyridine-6,3'-pyrrolo [2,3-
b) Preparation of extrudates, tablet formulations and tablets prepared therefrom comprising [pyridine] -3-carboxamide) (FIa-F)):
Using the general preparation set forth in Example I, 1.421 Kg of FIa-F (all
25.0 L Fielder Granulat), a compound of the formula Ia, wherein ^b ′ ′ is —F
or, impeller speed set to "high", chopper speed set to "high" 4.320 K
mixed with g of matrix polymer. While maintaining the impeller and chopper speeds
The granulator was charged with 0.300 Kg of TPGS over 5 minutes. This mixed material is at 158 ° C
Hot melt extrusion on a Thermo-Fisher 16 mm extruder set to provide a product temperature of 20 g / min, a powder feed rate of 20 g / min, and a die pressure maintained at 2 to 4 bars,
An extrudate of 4.52 Kg was obtained.

Thus, the prepared extrudate (3.3 Kg) is subjected to an impact blade set in the "forward" direction and an impeller speed set to the target 3000 rpm (2000 rpm to 6000 rpm),
Milled with a Fitzmill, screen diameter 000 (0, 20 ''). 60 crushed extrudates
Sift through a 0 micron screen to give a screened extrudate of 3.01 Kg. Sieve material (
3.0 Kg) part of sodium stearyl fumarate (0.05625 Kg), silicon dioxide (0.01875 Kg), microcrystalline cellulose (0.9750 Kg), powdered sodium chloride (0.750 Kg) and mannitol (1.950 Kg) And V-blender operating at 24 rpm.

Two aliquots (1.957 Kg) of the above-prepared tableting mixture were prepared according to plan P10165-
12 kP to 18 kP and 20 kP to 26 kP at a tablet target weight of 652.2 mg, respectively, on a Korsch XI 100 tablet molding machine equipped with a B (plain / plain) oval mold, upper and lower molds by 15.88 mm x 8.81 mm It was pressed into tablets corresponding to the hardness range.

USP 30 NF 25 No. 711 using simulated gastric fluid, 37 ° C., paddle speed 50 rpm
In the test according to section, the tablets were dissolved in a paddle stirred dissolution apparatus. These tablets are 2
90% release profile of FIa-F contained in tablets dissolved in less than 0 minutes, and aqueous HCl (pH 1.8), tested at 37 ° C., aqueous HCl as pH disintegrating medium (pH 1.8)
) At 37 ° C. in a standard disintegration test apparatus (Pharamatron DT50)
When tested using the disintegration test according to P 31-NF 26 chapter 701, it met the disintegration target of complete disintegration in less than 5 minutes.

Although the foregoing specification teaches the principles of the invention using the examples provided for the purpose of illustration, the practice of the invention resides in useful variations, adaptations, and within the scope of the following claims. And / or include all of the modifications.

Claims (21)

A pill,
(A) (i) a water soluble polymer matrix,
(Ii) a dispersant,
(Iii) a compound of formula I, or a pharmaceutically acceptable salt thereof:

An extrudate comprising Formula I, wherein “R ^a ” is independently —H or —F, and wherein said dispersant and compound of Formula I are dispersed in said polymer matrix;
(B) a tablet comprising a disintegration system,
Wherein said tablets have a hardness of about 12 kP to about 18 kP and an aqueous HC of 37 ° C.
A tablet wherein the tablet achieves complete disintegration in less than about 5 minutes in a standard tablet disintegration test according to US Patent 31-NF26 chapter 701 using l (pH 1.8). A pill,
(A) (i) a polymer matrix which is a water soluble polyvinyl pyrrolidone / vinyl acetate copolymer;
(Ii) a dispersant,
(Iii) a compound of formula I, or a pharmaceutically acceptable salt thereof:

An extrudate comprising Formula I, wherein “R ^a ” is independently —H or —F, and wherein said dispersant and compound of Formula I are dispersed in said polymer matrix;
(B) A tablet comprising powdered sodium chloride and a disintegration system comprising croscarmellose sodium. The tablet of claim 1, wherein the polymer matrix in the extrudate is a water soluble polyvinyl pyrrolidone / vinyl acetate (PVP-VA) copolymer. The tablet of claim 1, wherein the disintegrating system comprises powdered sodium chloride and croscarmellose sodium. The tablet of claim 2 wherein the disintegrating system comprises powdered sodium chloride and croscarmellose sodium in a 1: 1 weight ratio. The tablet has a hardness of about 12 kP to about 18 kP, and the tablet is a paddle stirrer equipped with a USP 2 paddle operated at 50 rpm in 900 ml of simulated gastric fluid (pH 1.8) at 37 ° C., USP 30. The tablet of claim 2 which, when subjected to a dissolution test in accordance with Section NF.sub.711, releases at least about 90% of the compound of Formula I contained in the tablet in less than about 20 minutes. In a paddle stirrer equipped with a USP 2 paddle, operated at 50 rpm, in 900 ml of simulated gastric fluid (pH 1.8) at 37 ° C., said tablets have a tensile strength of 1.75 MPa, USP 30 When subjected to dissolution testing in accordance with NF 25 Chapter 711:
3. The tablet of claim 2, which releases at least about 90% of the compound of Formula I contained in the tablet in less than about 20 minutes. The tablet according to any of claims 1 to 7, wherein the dispersing agent in the extrudate is d-alpha-tocopheryl polyethylene glycol succinate (TPGS). The compound of formula I is a compound of formula Ia or a salt thereof:

Formula Ia
The tablet according to any of claims 1 to 8, wherein "R ^b " is each -H, or "R ^b " is each -F. (A) mannitol, (b) colloidal silica, (c) microcrystalline cellulose, (d
The tablet according to any one of claims 1 to 8, further comprising sodium stearyl fumarate). Said API is (S) -N-((3S, 5S, 6R) -6-methyl-2-oxo-1-)
(2,2,2-trifluoroethyl) -5- (2,3,6-trifluorophenyl) piperidin-3-yl) -2′-oxo-1 ′, 2 ′, 5,7-tetrahydrospiro [ 10. The tablet of claim 8 or 9, which is cyclopenta [b] pyridine-6,3'-pyrrolo [2,3-b] pyridine] -3-carboxamide. Said API is (S) -N-((3S, 5S, 6R) -6-methyl-2-oxo-5-)
Phenyl-1- (2,2,2-trifluoroethyl) piperidin-3-yl) -2′-oxo-1 ′, 2 ′, 5,7-tetrahydrospiro [cyclopenta [b] pyridine-6,3
The tablet according to claim 8 or 9, which is' -pyrrolo [2,3-b] pyridine] -3-carboxamide. The extrudate is about 50 wt. %, Said extrudates being about 5 wt. % To about 2
3 wt. 13. A tablet according to any of the preceding claims, which is composed of% compound of formula I. The powdered sodium chloride may have (i) a d ₅₀ value less than about 210 microns, (ii) about 50
Having a d ₁₀ value less than a micron, and (iii) a d ₉₀ value less than about 470 microns,
A tablet according to any of the preceding claims. The water soluble polymer matrix of the extrudates comprises about 6: 4 polyvinyl pyrrolidone /
12. A tablet according to any of the preceding claims, which is a copolymer having a vinyl acetate monomer unit ratio. A formulation suitable for compression molding into tablets,
a) Water soluble polyvinyl pyrrolidone / vinyl acetate copolymer (PVP-VA copolymer) matrix and dispersed therein:
(I) Active compound of formula Ia, or pharmaceutically acceptable salt thereof:

Formula Ia
(Wherein all of R ^b is either —H or all of R ^b is —F,
In which R ^a is independently -H or -F);
(Ii) An extrudate composition comprising toceferol polyethylene glycol succinate (TPGS), wherein
The compound of Formula Ia comprises about 5 wt% to about 23 wt. %, Wherein TPGS comprises at least about 5 wt. % Of the extrudate composition,
A preparation as described above comprising b) (i) croscarmellose sodium and (ii) a disintegrating system comprising sodium chloride powder,
The disintegration system comprises about 20 wt. %, Said formulation. (A) mannitol, (b) colloidal silica, (c) microcrystalline cellulose, (d
B.) Sodium stearyl fumarate, said powdered sodium chloride having (i) a d ₅₀ value of less than about 210 microns, (ii) a d ₁₀ value of less than about 50 microns, and (ii
i) is characterized by _{d 90} value of less than about 470 microns, the formulation of claim 16. The compound of formula Ia: powdered sodium chloride: croscarmellose sodium in a weight ratio of 9:
18. The formulation of claim 16 or claim 17 which is 10:10. The compound of the formula Ia is (S) -N-((3S, 5S, 6R) -6-methyl-2-oxo-1- (2,2,2-trifluoroethyl) -5- (2,3) , 6-Trifluorophenyl) piperidin-3-yl) -2'-oxo-1 ', 2', 5,7-tetrahydrospiro [cyclopenta [b] pyridine-6,3'-pyrrolo [2,3-b ] Pyridine] -3-carboxamide, or (S) -N-((3S, 5S, 6R) -6-methyl-2-oxo-5
-Phenyl-1- (2,2,2-trifluoroethyl) piperidin-3-yl) -2'-
Oxo-1 ', 2', 5,7-tetrahydrospiro [cyclopenta [b] pyridine-6,
A method according to claim 16 which is 3'-pyrrolo [2,3-b] pyridine] -3-carboxamide.
One of the eight formulations. The extrudate is about 50 wt. Claim 16 to 1 present in an amount providing%.
One of the nine formulations. 21. A tablet made by pressing a formulation of any of claims 16 to 20 in a tablet press to provide a tablet having a tensile strength of about 175 MPa.

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